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PubMed1985

Preleukemic syndrome in elderly patients--report of 11 cases.

The preleukemic syndrome occurs mainly after middle age. We report 11 patients, aged 62 to 92 years, who presented with weakness, fatigue, malaise and pallor. Eight patients died; survival from the time of diagnosis was between 2 and 21 months. Two of them developed acute myelomonocytic leukemia. A third patient developed Philadelphia chromosome-negative chronic myeloid leukemia within 9 months. Serum unsaturated B12 binding capacity and transcobalamin I were elevated in this patient, preceding the transformation to chronic myeloid leukemia. Five other patients died from sepsis or pneumonia. All patients were anemic, and 10 were leukopenic. Bone marrow was hypocellular in 1 and hypercellular in 10 cases. Chromosomal studies were performed in five patients, with three showing abnormal findings: 47xx, trisomy 8 and a tetraploid karyotype 92xxyy5q-. No cytotoxic treatment should be given during the preleukemic phase until transformation to acute leukemia occurs. Since preleukemic patients are very susceptible to infections, early diagnosis of the condition is important, as is supportive care in the case of surgery.

Aged↗
PubMed1974

[Radioanalytical methods of determination in vitro of folates and vitamin B 12: diagnostic use in disorders of absorption and utilization].

The blood concentrations of vitamin B12 and folate, which are very useful in diagnosis of megaloblastic anemia and of these factors' dificiencies, are actually measured by precise, rapid, and specific competitive binding radioassays. Futher clinical advantages can be reached with the application of other in vitro radioisotope techniques, such as radioassay of IF, of antibodies anti-IF, of transcobalamins, and of FABP (folic acid binding protein). The major impact of the vitamin B12, folates and other related radioassays has been to permit more Hospitals and laboratories to do these determinations, replacing the more time-consuming, relatively imprecise, and often artifactual microbiological assays.

Anemia, Megaloblastic↗
PubMed1974

Selective vitamin B12 malabsorption in two siblings.

Two siblings with megaloblastic anemia responsive to parenteral vitamin B(12) were studied to elucidate the cause of the B(12) deficiency. Gastric juice from both contained acid and functional intrinsic factor. Serum contained transcobalamin II and lacked antibodies to intrinsic factor. Schilling tests showed vitamin B(12) malabsorption uncorrected by hog intrinsic factor or pancreatic extract. Other parameters of small intestinal function were normal. Proteinuria was initially present in both but cleared in one following treatment with B(12). These patients with "familial selective vitamin B(12) malabsorption" are the first reported from Canada. Only 37 cases have been reported in the world literature to date.

Anemia, Macrocytic↗
PubMed1979

Congenital defect in intracellular cobalamin metabolism resulting in homocysteinuria and methylmalonic aciduria. I. Case report and histopathology.

The case is described of an infant who suffered from progressive, severe dystrophy, hemolytic and megaloblastic anemia, hematuria, proteinuria and slight uremia. He died at 4 months of age following two acute episodes of heart failure. Abnormally increased excretion of methylmalonate and homocystine was detected by our screening program for metabolic disorders. Amino acid analyses showed that the plasma and urine levels of methionine were very low whereas those of cystathionine were raised. Vitamin B12 deficiency, malabsorption or abnormal cobalamin transport were excluded by a normal serum total cobalamin and normal transcobalamins. These findings suggested a congenital error of cobalamin metabolism. Treatment with vitamin B12 resulted in a biochemical though not a clinical response. Postmortem examination revealed severe vascular lesions with changes in the kidney characteristic of thrombotic microangiopathy supporting a diagnosis of hemolytic-uremic syndrome. It is assumed that the elevated plasma homocysteine induced the vascular lesions by causing detachment of endothelium.

Blood Vessels↗
PubMed1977

Comparison of toadfish-serum competitive binding and microbiologic assays of vitamin B12.

Toadfish serum (TFS) offers several advantages over other proteins as the binder in a competitive-binding assay for vitamin B12. It is unaffected by pH changes in the range 5.6-9.4 or by the addition of human serum albumin. Prolonged incubation with charcoal does not disrupt the TFS-cyanocobalamin bond, and the addition of albumin as a protein source in the standard tubes was proven unnecessary. The binding capacity of TFS does not increase significantly with increasing concentrations of cyanocobalamin as does the binding capacity of intrinsic factor, normal serum, or transcobalamin I. A single extract was prepared from each of 44 sera and measured for vitamin B12 content simultaneously by the TFS assay and the conventional microbiologic method using Lactobacillus leichmannii. The values obtained with TFS were in each instance higher than those obtained by the microbiologic assay (p less than 0.001).

Animals↗
PubMed1982

[Phagocytes and phagocytosis 100 years after Metchnikoff. A current picture of the neutrophil leukocyte].

The observation of the amoebocytes of primitive organisms led ELIAS METSCHNIKOFF in 1882 to the idea that blood phagocytes--neutrophilic leukocytes in particular--could constitute an anti-microbial defense system. This was the beginning of the phagocyte theory which METSCHNIKOFF developed over many years and which in essence is still valid. The author sets out to provide an updated view of the neutrophil. Circulating neutrophils are end-cells. They develop in the bone marrow by a relatively long maturation process during which the characteristic azurophil and specific granules are formed. The granules are stored organelles. The azurophil granules contain microbicidal enzymes, i.e. myeloperoxidase and lysozyme, together with a large number of acid hydrolases and neutral proteases. The specific granules contain lysozyme, a collagenase, lactoferrin and transcobalamines. By subcellular fractionation a third kind of storage organelle has recently been found which is characterized by its gelatinase content. Circulating neutrophils are activated on microbial invasion--first in the blood, by chemotactic factors formed at the site of infection, and subsequently by the microbes themselves which are phagocytosed by the immigrating neutrophils. Chemotactic factors lead to directed migration and induce the secretion of enzymes which presumably facilitate this process. Phagocytosis results in the mobilization of neutrophil products in large quantities. The contact between the cell and the microorganism activates in the neutrophil membrane an oxidase which produces superoxide, and a phospholipase which releases arachidonic acid. The latter is then oxidized by cyclooxygenase and lipoxygenase. There is also massive liberation of enzymes from all three storage compartments. The production of superoxide is the essential process for the killing of a large variety of microorganisms.

Allergy and Immunology↗
PubMed1984

The uptake of vitamin B12 by human lymphocytes and the relationships to the cell cycle.

The phase of the cell cycle permitting transcobalamin II (TC II) mediated entry of cobalamin (Cbl) into human lymphocytes was determined under several conditions. (1) Little was taken up by resting peripheral blood lymphocytes (PBL). (2) Uptake was enhanced by stimulation of PBL by culture with a mitogen. (3) This increase in capacity for uptake took place simultaneously during 3 days of culture with the increase in capacity to synthesize DNA. (4) Hydroxyurea inhibited both DNA synthesis and TC II-Cbl uptake. (5) As culture was prolonged and the cells passed beyond the phase of most active division, DNA synthesis and Cbl uptake declined sharply. (6) The increased capacity to take up Cbl after stimulation was determined, at least in part, by increased receptor activity for TC II-Cbl. (7) Internalization of the Cbl was also increased. (8) Simultaneously with the increasing DNA synthesis, the cells increased in the activity of the Cbl-dependent methionine synthetase (MS). (9) MS activity subsequently fell during longer culture. Thus PBL can take in Cbl only during a narrow "window" in the cell cycle. This window is associated with the period of most active DNA synthesis and at a time when one coenzyme of Cbl, MeCbl, is the most active.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1981

Vitamin B12-dependent replication of L1210 mouse leukemia cells. A model system for cobalamin-folate inter-relationships.

L1210 mouse leukemia cells were made cobalamin-deficient by propagation in a medium from which cyanocobalamin was omitted and fetal bovine serum (containing protein-bound cobalamins) was replaced by bovine serum albumin. These cobalamin-deficient cells exhibited a normal replication time of 12 h, provided that the medium contained excess folate or 5-formyltetrahydrofolate. The cells responded poorly, however, to 5-methyltetrahydrofolate unless exogenous cobalamin was added. A cobalamin dependency was also observed when low levels of folate or 5-formyltetrahydrofolate were used. With 5-methyltetrahydrofolate, optimal stimulation of growth was observed with free and transcobalamin-II-bound cobalamin at 4,000 pM and 2 pM, respectively. Under cobalamin-replete conditions, cells contained 2,000 to 4,000 molecules of cobalamin/cell, and in the deficient state, this value declined to less than 10 molecules/cell; optimal replication on 5-methyltetrahydrofolate required approximately 180 molecules/cell. Cobalamin-deficient cells cultured in the absence of folate reached an arrested state from which limited replication could be induced by the addition of aquacobalamin; normal replication was induced by aquacobalamin plus 5-methyltetrahydrofolate. Results of this investigation are interpreted in terms of the requirement for tetrahydrofolate in cell replication and the production of this compound from folate and 5-formyltetrahydrofolate (via cobalamin-independent pathways) and from 5-methyltetrahydrofolate (via the cobalamin-dependent methionine synthetase).

Animals↗
PubMed1981

[Vitamins in metabolic diseases].

Several vitamins have been demonstrated to interfere with the pathogenesis of some metabolic diseases, mainly by three different mechanisms: 1) vitamin malabsorption, 2) errors in vitamin metabolism, 3) vitamin dependent syndromes. The latter is due to a deficiency of the apoenzyme whose coenzyme is the vitamin itself. In this case pharmacological, instead of nutritional doses of the vitamin may be needed. The vitamins which interfere with inborn metabolic errors are reviewed; for each vitamin the corresponding diseases which may be treated are indicated. The vitamins are: 1) thiamine (leucinosis); b) nicotinic acid (hyperlipoproteinemia); c) biotin (beta-methyl-crotonyl-glycinuria, propionic aciduria); d) pyridoxine (infantile convulsions, familial pyridoxine responsive anemia, homocystinuria, cystathioninuria, xanthurenicaciduria); e) cobalamins (congenital intrinsic factor deficiency, cobalamin malabsorption, transcobalamin deficiency, methylmalonic aciduria) f) folic acid (congenital folic acid malabsorption, formimino-transferase deficiency, methylenetetrahydrofolic reductase deficiency, Lesch-Nyhan syndrome); g) vitamin D (phosphatic diabetes, Prader's type rickets, Albright's syndrome; essential hereditary hypophosphatemia, etc). It is noteworthy that the vitamin therapy of these diseases, not only corrects the metabolic errors, but can also promote the healing or the amelioration of the psycho-physical growth, of central nervous system alterations and of other lesions.

Biotin↗
PubMed1980

Studies in B12-deficient monkeys with combined system disease. I. B12-deficient patterns in bone marrow deoxyuridine suppression tests without morphologic or functional abnormalities.

A colony of rhesus monkeys made vitamin B12 deficient through dietary deprivation has been maintained since 1970. Deficient animals regularly develop neurologic lesions histologically, ultrastructurally, and topographically indistinguishable from those of human subacute combined degeneration but have failed to develop overt hematologic changes. No megaloblastic alterations, other evidence of impaired blood cell production, or subtle differences in mean red cell size are found. dU suppression tests on bone marrow were performed to determine whether functional B12 deficiency existed. All B12-deficient monkeys had markedly abnormal dU suppression test results after more than 10 months of B12 depviation, corrected by addition of B12 in vitro, whereas controls remained normal. Reasons for these disparate findings are considered, including species differences in metabolism of cobalamin analogues, cobalamin, and transcobalamins; the sensitivity of the dU test; the fact that ability to utilize preformed nucleotides may be greater in monkeys than in humans.

Animals↗
PubMed1994

Correlations between acetaldehyde-modified haemoglobin, carbohydrate-deficient transferrin (CDT) and haematological abnormalities in chronic alcoholism.

Serum levels of carbohydrate-deficient transferrin (CDT), the proportions of eight haemoglobin fractions separated by cation exchange liquid chromatography, indices of liver function and various haematological parameters were determined in most of a group of 49 chronic alcoholics who had misused alcohol for at least the preceding 3 months and in 15 healthy non-alcoholic control subjects. The percentages of alcoholics giving abnormally high values for gamma-glutamyl transferase (GGT) activity, CDT levels, GGT activity or CDT levels or both, and aspartate aminotransferase (AST) activity were, respectively, 73.0, 71.0, 87.1 and 64.4. The percentages of patients giving abnormally high values for the proportion of HbA1a, proportion of HbA1ach, proportion of HbA1a or HbA1ach or both, MCH, MCV and red cell distribution width (RDW) were, respectively, 46.8, 25.5, 55.3, 55.3, 36.2 and 29.8. Reduced values for the red cell folate concentration, lymphocyte count and platelet count were found in 36.2%, 6.4% and 17.0%, respectively, of the alcoholics. When compared with the control subjects, the group of alcoholics showed statistically significant increases in the mean values for the MCV, MCH, MCHC and RDW and statistically significant decreases in the mean values for the haemoglobin distribution width (HDW) and the logarithms of the holo-transcobalamin II concentrations and the platelet count. The logarithms of the CDT values correlated directly with the MCV and MCH and inversely with the logarithms of the lymphocyte or platelet counts and the HDW, suggesting but not proving that the haematological changes in chronic alcoholism may be at least partly related to defective glycosylation of the constituents of developing blood cells or, possibly, of haemopoietic growth factors.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaldehyde↗
PubMed1994

Transcytosis and processing of intrinsic factor-cobalamin in Caco-2 cells.

Intracellular events within enterocytes following receptor-mediated endocytosis of intrinsic factor-cobalamin (IF-Cbl) are poorly understood. We have examined the fate of IF and Cbl in filter-grown Caco-2 cells which express both IF receptors and transcobalamin II and which transcytose Cbl. Uptake of IF-Cbl from the apical surface leads to the intracellular accumulation of Cbl in a process that reaches an equilibrium between internalization and secretion only after a 20-h continuous incubation. Transcytosed Cbl is detectable in the basolateral medium 4 h after the onset of endocytosis. Cbl is released from the basolateral surface with the same kinetics irrespective of from which cell surface endocytosis of IF-Cbl took place. Following uptake, internalized IF is degraded with a half-time of 4 h. Leupeptin causes a partial block in the proteolysis of IF, an intracellular accumulation of Cbl bound to IF, and a decrease in transcytosis of Cbl. Finally, an analysis of intracellular Cbl during transcytosis shows that free Cbl is present within cells during transcytosis.

Biological Transport↗
PubMed1994

[Absorption, distribution and excretion of vitamin B12].

In our first communication, the complexity of vitamin B12 digestive transport was considered. This second presentation demonstrates the route of the vitamin in the body. As cobalamin or vitamin B12 has existed for Four Billion Years, they figure without any doubt amongst those molecules which have the most complex structure. The rarity of an architecture organised around a cobalt atom confirms their high level of originality. Their exceptional character is reflected in their cycle such as for mammals and for man where the intervention of binders, such as intrinsic factor, transcobalamin and haptocorrin is necessary for transporting them. As far as cellular metabolism is concerned, it is especially loaded sometimes with folates in the transfer of the methyl group. The Molecules are spiked with hydrophobic sites. Their membrane transfer is facilitated by several types of receptors. The intestinal absorption, which appears to require the presence of two receptors and two transporters, remains for the moment a unique assimilation model. The very probable existence of an enterohepatic cycle as well as a renal reabsorption saves this molecule, itself synthesised by microorganisms only.

Humans↗
PubMed1977

Detection of genetic variation with radioactive ligands. I. Electrophoretic screening of plasma proteins with a selected panel of compounds.

To detect new genetic variation in human plasma proteins, a panel of 63 radioactive substances were screened as potential radioligands using polyacrylamide gel electrophoresis (PAGE) and autoradiography. Vitamins, hormones, drugs, amino acids, purines, pyrimidines, sugars and lipids labeled with 14C or other radionuclides were among those substances tested. A majority bound to albumin and a smaller fraction to prealbumins and lipoproteins. Several vitamins and hormones bound to specific alpha and beta globulins. (1) Electrophoretic polymorphisms of vitamin D-binding protein (group-specific component), a vitamin B12-binding protein (transcobalamin II), and thyroxine-binding alpha-globulin are described elsewhere. (2) Testosterone-binding beta-globulin (TeBG) showed an electrophoretic polymorphism in Caucasians and a possible deficiency allele. (3) Transcortin showed an electrophoretic doublet in all persons tested but no electrophoretic variation. (4) A protein binding derivative of norepinephrine or epinephrine was identified as transferrin. (5) A nonpolymorphic protein running cathodal to albumin and binding a derivative of riboflavin was tentatively identified as a fraction of albumin with mobility altered as a result of interaction with the ligand.

Adult↗
PubMed1997

Selective cobalamin malabsorption and the cobalamin-intrinsic factor receptor.

The disease is characterised by cobalamin (Cbl) deficiency in children 0-5 years old, causing failure to thrive, infections, megaloblastic anaemia, neuropathy, and mild general malabsorption; slight proteinuria is common. Cbl injections produce remission, but Cbl malabsorption and proteinuria persist. About 250 cases have been reported. Dogs also have it. The heredity is autosomal and recessive. The physiological and pathological absorption mechanisms are described: Cbl liberated from food by digestion is first bound to haptocorrin, but in the intestine it is transferred to intrinsic factor. In the ileum the complex attaches to a receptor on the enterocytes; this requires neutral pH and Ca2+. The receptor is a membrane-bound glycoprotein consisting of multiple subunits. The receptor-ligand complex is endocytosed and degraded in lysosomes, and the vitamin is transferred to transcobalamin which carries it to tissues. The same receptor is strongly expressed in the kidneys, but urine also contains its activity which can be assayed for diagnosis. The basic lesion is an error in the ileal receptor. In the affected dogs the synthesised receptor is retained intracellularly. Urine and ileal biopsies from human cases contained little receptor but it had conserved affinity for the ligand. Recently examined Arab patients did not excrete reduced amounts of the receptor. Apparently, the disease has subsets, such as different structural errors in the receptor and possibly faulty transport inside the enterocyte. The cause of the proteinuria is unknown but kidney damage due to severe Cbl deficiency and an error in a multiligand renal receptor are among the possibilities.

Animals↗
PubMedDate not supplied

Receptors of the low density lipoprotein (LDL) receptor family in man. Multiple functions of the large family members via interaction with complex ligands.

The LDL receptor family members are endocytic receptors composed of repeated protein modules, including clusters of ligand binding LDL receptor class A (LA) repeats. The large (approximately 600 kDa) members LRP and megalin bind numerous structurally unrelated and often complex ligands at different combinations of sites. LRP is expressed in a wide but restricted set of cell types including hepatocytes, macrophages, smooth muscle cells, and neurons of the CNS. Megalin is expressed in various epithelia including proximal kidney tubules, intestine, and ependymal cells. The two receptors share a multitude of ligands, and their function in vivo is therefore to a large extent determined by their expression pattern. For example, both receptors can endocytose lipoproteins, but this function appears mainly relevant for LRP. In addition, LRP helps regulating urokinase receptor expression on the cell surface via ligand-mediated internalization followed by return of the naked urokinase receptor to the cell surface. Both receptors also have specialist functions. LRP is specific for binding of alpha2-macroglobulin-proteinase complexes and provides clearance of the complexes and of peptides, e.g. cytokines, associated with the complex. Megalin has important functions in vitamin B12 homeostasis since it specifically mediates uptake of the vitamin B12-transcobalamin complex and helps building a storage pool for the vitamin in the kidneys. Moreover, megalin binds cubilin, the recently identified receptor for B12-intrinsic factor complex, thus providing a mechanism for uptake of dietary vitamin B12. Finally, megalin specifically mediates uptake of apolipoprotein J/clusterin, a binding protein for the Abeta peptide implicated in Alzheimer's disease. The binding of multiple complex ligands that belong to distinct physiological systems provides a challenge in future studies aiming at elucidating the role of LRP and megalin in disease mechanisms.

Humans↗
PubMed2005

Oral cyanocobalamin supplementation in older people with vitamin B12 deficiency: a dose-finding trial.

BACKGROUND: Supplementation with high doses of oral cobalamin is as effective as cobalamin administered by intramuscular injection to correct plasma markers of vitamin B(12) deficiency, but the effects of lower oral doses of cobalamin on such markers are uncertain. METHODS: We conducted a randomized, parallel-group, double-blind, dose-finding trial to determine the lowest oral dose of cyanocobalamin required to normalize biochemical markers of vitamin B(12) deficiency in older people with mild vitamin B(12) deficiency, defined as a serum vitamin B(12) level of 100 to 300 pmol/L (135-406 pg/mL) and a methylmalonic acid level of 0.26 mumol/L or greater. We assessed the effects of daily oral doses of 2.5, 100, 250, 500, and 1000 mug of cyanocobalamin administered for 16 weeks on biochemical markers of vitamin B(12) deficiency in 120 people. The main outcome measure was the dose of oral cyanocobalamin that produced 80% to 90% of the estimated maximal reduction in the plasma methylmalonic acid concentration. RESULTS: Supplementation with cyanocobalamin in daily oral doses of 2.5, 100, 250, 500, and 1000 mug was associated with mean reductions in plasma methylmalonic acid concentrations of 16%, 16%, 23%, 33%, and 33%, respectively. Daily doses of 647 to 1032 mug of cyanocobalamin were associated with 80% to 90% of the estimated maximum reduction in the plasma methylmalonic acid concentration. CONCLUSION: The lowest dose of oral cyanocobalamin required to normalize mild vitamin B(12) deficiency is more than 200 times greater than the recommended dietary allowance, which is approximately 3 mug daily.

Administration, Oral↗
PubMed1993

Subacute combined degeneration with high serum vitamin B12 level and abnormal vitamin B12 binding protein. New cause of an old syndrome.

Subacute combined degeneration of the spinal cord due to vitamin B12 deficiency invariably has been associated with a low serum vitamin B12 level. We describe a young man who presented with a unique syndrome of subacute combined degeneration associated with high serum vitamin B12 level, low red blood cell vitamin B12 level, and an abnormal plasma vitamin B12-binding protein. Uptake of cobalamin by his leukocytes in vitro was inhibited by his own but not by normal control plasma. Intensive hydroxocobalamin (vitamin B12) treatment was associated with clinical and electrophysiologic recovery accompanied by normalization of mean corpuscular volume, red blood cell vitamin B12 level, plasma homocysteine, and urinary methylmalonic acid. The subacute combined degeneration was probably precipitated by treatment with folic acid as the significance of his high serum vitamin B12 level was not apparent when he first presented with megaloblastic anemia 3 years earlier. To our knowledge, this is the first example of neurologic disease associated with high serum vitamin B12 level and provides further evidence that sometimes a serum vitamin B12 level may not be a reliable guide to vitamin B12 deficiency.

Adult↗